Physiology and Pathophysiology of Apolipoprotein E receptor-2 splicing in Alzheimer's disease
Physiology and Pathophysiology of Apolipoprotein E receptor-2 splicing in Alzheimer's disease
批准号:
9159262
负责人:
Joachim J Herz
金额:
$202.48万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-07-15 至 2021-08-31
关键词:
AddressAffectAgeAllelesAlternative SplicingAlzheimer&aposs DiseaseAmericanAmyloidAmyloid beta-Protein PrecursorApolipoprotein EBehaviorBrainCCL4 geneCarrier ProteinsCell NucleusCholesterolCleaved cellClinicalCognitionCognitive deficitsCytoplasmic TailDendritic SpinesDue ProcessElderlyEndocytosisEndosomesEventExonsExtracellular DomainFailureFrightFunctional disorderGene ExpressionGene FamilyGenesGenetic TranscriptionGlutamate ReceptorHippocampus (Brain)HomeostasisHumanImpaired cognitionKnock-in MouseKnock-outKnockout MiceLDL-Receptor Related Protein 1Late Onset Alzheimer DiseaseLearningLeftLigandsLinkLow Density Lipoprotein ReceptorMediatingMemoryMemory LossMetalloproteasesModelingModificationMusNeurodegenerative DisordersNeuronsNeurotransmittersPathogenesisPeptidesPeripheralPhysiologicalPhysiologyProcessProtein IsoformsProteinsProteolysisProteolytic ProcessingRNA SplicingReceptor ActivationReceptor GeneRecyclingRegulationReportingResistanceRisk FactorsRoleSignal TransductionSourceStructureSynapsesTestingTherapeuticToxic effectTrademarkVLDL receptorVariantVertebral columnWorkamyloid formationamyloid precursor protein processingapolipoprotein E receptor 2apolipoprotein E-4densityextracellularfear memorygamma secretaseglycosylationhigh riskin vivomembermutantneurotransmissionnovel therapeuticsoverexpressionpreventprogressive neurodegenerationprotective effectreceptorsugarsynaptic functionsynaptogenesistrafficking
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
According to the most recent Alzheimer's Association report, 2015 Alzheimer's Disease Facts and Figures,
one out of nine Americans over the age of 65 has Alzheimer's Disease (AD) and an estimated 40-65% of them
carry at least one copy of the ε4 allele of gene for a cholesterol transport protein, apolipoprotein E (ApoE).
Despite being one of the highest risk factors for AD (second only to age), the mechanism by which ApoE4
increases AD occurrence is unknown. ApoE transports cholesterol to neurons via ApoE receptors, which are
members of the low density lipoprotein (LDL) receptor gene family. Some of these ApoE receptors, i.e. LRP1,
Apoer2, VLDL receptor (Vldlr), and Lrp4, are intrinsic components of central and peripheral synapses, where
they serve as essential regulators of neurotransmission through cytoplasmic signaling and neurotransmitter
trafficking.
The progressive neurodegeneration in AD first presents as memory loss brought on by synaptic
dysfunction. Amyloid-β (Aβ), the central component in the trademark plaques that build up in the brains of
people with AD, are a product of the amyloid precursor protein, APP, and a likely source of this early
dysfunction. We have shown previously that Aβ-induced synaptic suppression can be prevented through ApoE
receptor activation and ApoE4 selectively impairs this synaptoprotective function by sequestering the ApoE
receptor, Apoer2. Apoer2, an essential CNS ApoE receptor, is endogenously expressed in multiple
alternatively spliced forms, indicating a physiological need for functionally diverse forms of the receptor. We
have found that differential splicing of an extracellular O-glycosylation domain dramatically alters Apoer2
abundance, synaptic function and fear memory. Apoer2 can also modify the formation of Aβ through multiple
interactions with APP that effect APP processing. Therefore, understanding the regulation and function of
Apoer2 is central to understanding the mechanisms by which ApoE4 causes synaptic dysfunction in AD.
Accumulating evidence has identified Apoer2 as a key regulator of synaptic homeostasis. In this
application, we propose to investigate the consequences of the two main physiological splicing events of
Apoer2 on gene expression, protein interactions, behavior and cognition. In Aim 1 we will employ Apoer2-
deficient mice and mice expressing various splice forms of Apoer2 to explore how Apoer2 regulates gene
expression. In Aim 2, we will explore the protein interactome of these Apoer2 isoforms and probe how the
various ApoE isoforms affect their trafficking and signaling, as well as their ability to regulate APP processing.
In Aim 3, we will explore how endogenous Apoer2 splice variants modify behavior and cognition and how they
affect cognitive deficits in mice with human ApoE isoforms or Aβ-overproduction.
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Physiology and Pathophysiology of Apolipoprotein E receptor-2 splicing in Alzheimer's disease
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批准号:10076307
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项目类别:
-
资助金额:$39.72万
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财政年份:2016
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负责人:Joachim J Herz
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依托单位:
2014 Neurobiology of Brain Disorders Gordon Research Conference & Gordon Research
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批准号:8714546
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项目类别:
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资助金额:$5.0万
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财政年份:2014
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负责人:Joachim J Herz
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依托单位:
Cell Signaling, Membrane Cholesterol, and Lipoprotein Receptors
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批准号:7217722
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项目类别:
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资助金额:$56.48万
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财政年份:2007
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负责人:Joachim J Herz
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依托单位:
APO E Receptors and Modulation of Fast Axonal Transport
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批准号:6710581
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项目类别:
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资助金额:$37.05万
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财政年份:2002
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负责人:Joachim J Herz
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依托单位:
APO E Receptors and Modulation of Fast Axonal Transport
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批准号:7026938
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项目类别:
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资助金额:$36.18万
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财政年份:2002
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负责人:Joachim J Herz
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依托单位:
APO E Receptors and Modulation of Fast Axonal Transport
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批准号:6623050
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项目类别:
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资助金额:$37.05万
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财政年份:2002
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负责人:Joachim J Herz
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依托单位:
APO E Receptors and Modulation of Fast Axonal Transport
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批准号:6460608
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项目类别:
-
资助金额:$37.05万
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财政年份:2002
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负责人:Joachim J Herz
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依托单位:
APO E Receptors and Modulation of Fast Axonal Transport
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批准号:6855711
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项目类别:
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资助金额:$37.05万
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财政年份:2002
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负责人:Joachim J Herz
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依托单位:
Metabolism of the VLDL receptor and ApoE receptor 2
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批准号:8606229
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项目类别:
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资助金额:$38.96万
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财政年份:2000
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负责人:Joachim J Herz
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依托单位:
Metabolism of the VLDL receptor and ApoE receptor 2
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批准号:8213541
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项目类别:
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资助金额:$39.68万
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财政年份:2000
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负责人:Joachim J Herz
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依托单位:
Metabolism of the VLDL receptor and ApoE receptor 2
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批准号:7781745
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项目类别:
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资助金额:$39.63万
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财政年份:2000
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负责人:Joachim J Herz
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依托单位:
LDL RECEPTOR GENE FAMILY
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批准号:6323373
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项目类别:
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资助金额:$50.39万
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财政年份:2000
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负责人:Joachim J Herz
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依托单位:
METABOLISM OF THE VLDL RECEPTOR AND APOE RECEPTOR 2
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批准号:6499022
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项目类别:
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资助金额:$27.63万
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财政年份:2000
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负责人:Joachim J Herz
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依托单位:
Metabolism of the VLDL receptor and ApoE receptor 2
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批准号:7009614
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项目类别:
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资助金额:$34.28万
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财政年份:2000
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负责人:Joachim J Herz
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依托单位:
METABOLISM OF THE VLDL RECEPTOR AND APOE RECEPTOR 2
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批准号:6704221
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项目类别:
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资助金额:$29.29万
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财政年份:2000
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负责人:Joachim J Herz
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依托单位:
Metabolism of the VLDL receptor and ApoE receptor 2
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批准号:7568796
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项目类别:
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资助金额:$33.28万
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财政年份:2000
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负责人:Joachim J Herz
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依托单位:
Metabolism of the VLDL receptor and ApoE receptor 2
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批准号:8011517
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项目类别:
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资助金额:$39.63万
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财政年份:2000
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负责人:Joachim J Herz
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依托单位:
METABOLISM OF THE VLDL RECEPTOR AND APOE RECEPTOR 2
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批准号:6027996
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项目类别:
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资助金额:$25.34万
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财政年份:2000
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负责人:Joachim J Herz
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依托单位:
METABOLISM OF THE VLDL RECEPTOR AND APOE RECEPTOR 2
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批准号:6629041
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项目类别:
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资助金额:$28.45万
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财政年份:2000
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负责人:Joachim J Herz
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依托单位:
Metabolism of the VLDL receptor and ApoE receptor 2
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批准号:7175469
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项目类别:
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资助金额:$33.28万
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财政年份:2000
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负责人:Joachim J Herz
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依托单位:
海外基金